Delving into the Latest Updates on Nolpitantium besilate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

NK1R

Mechanism

NK1R antagonists(Neurokinin 1 receptor antagonists)

Therapeutic Areas

Immune System DiseasesDigestive System Disorders

Active Indication-

Inactive Indication

Colitis, Ulcerative

Originator Organization

Sanofi

Active Organization-

Inactive Organization

Sanofi

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC43H50Cl2N2O5S

InChIKeyPQRLQZNKDQQMBC-LSYPWIJNSA-M

CAS Registry155418-06-7

Fever elicited by bacterial lypopolyssacharide (LPS) is mediated by pro-inflammatory cytokines, which activate central mediators and regulate the hypothalamic temperature setpoint. This response is often accompanied by morphological changes involving the extracellular matrix, neurons and glial cells, with significant health impacts. The NK1 receptor is involved in the febrile response induced by LPS but its effects over the extracellular matrix in the context of neuroinflammation remain unknown. The present work aims to clarify the extracellular changes associated with NK1 signaling in LPS-induced fever. Male Wistar rats were exposed to LPS intraperitoneally. Experimental groups were pre-treated intracerebroventricularly with the NK1 selective inhibitor SR140333B or saline. Histological changes involving the brain extracellular matrix were evaluated using hematoxylin and eosin, Mason's trichrome, picrosirius, alcian blue, periodic acid Schiff's stains. The expression of matrix metalloproteinase 9 (MMP9) was studied using confocal microscopy. Fever was accompanied by edema, perivascular lymphoplamacytic and neutrophylic infiltration, spongiosis and MMP9 overexpression. SR140333B significantly reduced LPS-induced fever (p < 0.0001), MMP9 overexpression (p < 0.01) and associated histological changes. These results contribute to characterize cerebral extracellular matrix changes associated with LPS-induced fever. Overall, the present work supports a role for NK1 receptor in these neuroinflammatory changes, involving MMP9 overexpression, edema and leukocytic infiltration.

01 Nov 2021·Advanced ScienceQ1 · MATERIALS SCIENCE

A Novel Mechanism of Endoplasmic Reticulum Stress‐ and c‐Myc‐Degradation‐Mediated Therapeutic Benefits of Antineurokinin‐1 Receptor Drugs in Colorectal Cancer

Q1 · MATERIALS SCIENCE

ArticleOA

Author: Fu, Caiyun ; Cao, Yihai ; Ma, Junjie ; Yan, Zhibin ; Meng, Yueming ; Shi, Yue ; Shao, Gang ; Wang, Xi ; Cheng, Xurui ; Wang, Lingfei ; Wang, Yong ; Hong, Xiangyu ; Zhang, Qiyu ; Kang, Jian

AbstractThe neurokinin‐1 receptor (NK‐1R) antagonists are approved as treatment for chemotherapy‐associated nausea and vomiting in cancer patients. The emerging role of the substance P‐NK‐1R system in oncogenesis raises the possibility of repurposing well‐tolerated NK‐1R antagonists for cancer treatment. This study reports that human colorectal cancer (CRC) patients with high NK‐1R expression have poor survival, and NK‐1R antagonists SR140333 and aprepitant induce apoptotic cell death in CRC cells and inhibit CRC xenograft growth. This cytotoxicity induced by treatment with NK‐1R antagonists is mediated by induction of endoplasmic reticulum (ER) stress. ER stress triggers calcium release, resulting in the suppression of prosurvival extracellular signal‐regulated kinase (ERK)‐c‐Myc signaling. Along with ER calcium release, one ER stress pathway mediated by protein kinase RNA‐like ER kinase (PERK) is specifically activated, leading to increased expression of proapoptotic C/EBP‐homologous protein (CHOP). Moreover, NK‐1R antagonists enhance the efficacy of chemotherapy by increasing the sensitivity and overcoming resistance to 5‐fluorouracil in CRC cells through the induction of sustained ER stress and the consequent suppression of ERK‐c‐Myc signaling both in vitro and in vivo. Collectively, the findings provide novel mechanistic insights into the efficacy of NK‐1R antagonists either as a single agent or in combination with chemotherapy for cancer treatment.

01 Feb 2021·NeuroscienceQ3 · MEDICINE

Presynaptic NK1 Receptor Activation by Substance P Suppresses EPSCs via Nitric Oxide Synthesis in the Rat Insular Cortex

Q3 · MEDICINE

Article

Author: Kobayashi, Masayuki ; Tsuda, Hiromasa ; Takei, Hiroki ; Nakaya, Yuka ; O'Hashi, Kazunori ; Matsumura, Sachie ; Yamamoto, Kiyofumi ; Shirakawa, Tetsuo ; Kaneko, Keisuke

Substance P (SP) regulates inhibitory synaptic transmission mediated by GABA_A receptors in the cerebral cortex; however, SP-mediated regulation of excitatory synaptic transmission remains poorly understood. We performed whole-cell patch-clamp recordings from pyramidal neurons to examine the effects of SP on excitatory postsynaptic currents (EPSCs) mediated via AMPA receptors in the insular cortex (IC), which is involved in nociceptive information processing. First, EPSCs evoked by minimal electrical stimulation (eEPSCs) including stepwise EPSCs and failure events, were examined. SP dose-dependently suppressed mean eEPSC amplitude, partially due to an increase in the failure rate of eEPSCs. The SP-induced suppression of eEPSCs was accompanied by an increase in the paired-pulse ratio and was inhibited by the preapplication of SR140333, an NK1 receptor antagonist. [Sar⁹,Met(O₂)¹¹]-substance P, an NK1 receptor-selective agonist, mimicked the effects of SP on eEPSCs and decreased the frequency of miniature EPSCs (mEPSCs) without changing the average mEPSC amplitude. Considering that most NK1 receptors in the cerebral cortex are expressed in nitric oxide synthase (NOS)-positive GABAergic neurons, the SP-induced suppressive effect on EPSCs may be mediated by nitric oxide (NO) in this subtype of GABAergic neurons. NO imaging using the fluorescent probe DAX-J2 Red supports this hypothesis: SP increased the fluorescence intensity of DAX-J2 Red in some GABAergic neurons. Furthermore, both L-NAME, an NOS inhibitor, and PTIO, an NO scavenger, diminished the SP-induced suppression of eEPSCs. These results suggest that the activation of presynaptic NK1 receptors contributes to SP-induced eEPSC suppression by activating the NO synthesis pathway in GABAergic neurons. (246 words).

100 Deals associated with Nolpitantium besilate

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05790

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis, Ulcerative	Phase 2	CA	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	SG	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	CZ	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	EE	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	BR	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	CL	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	AR	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	ES	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	IT	Sanofi	01 Apr 2005
Colitis, Ulcerative	Phase 2	ZA	Sanofi	01 Apr 2005